2. • Why neuromodulation for the
treatment of chronic pain?
• What do we know about
chronic pain?
3. • Chronic pain has a different
pathophysiology as compared to acute
pain syndromes
• It is associated with plastic changes in the
nervous system - leading to the
phenomenon of central and peripheral
sensitization
4. Development of spontaneous activity in primary afferents
Increase of mechanosensitiviy
Activation of protein kinase C facilitates the response to sensory
neurons to capsaicin
Inflammation -
production of
multiple mediators -
bind to G-protein
receptors - activation
of second
messengers
(alterations in gene
expression and
receptors
Primary nociceptors mostly terminate in the spinal
cord - second-order neurons exhibit plasticity
dependent activity - repetitive activity induces long-
lasting facilitation in the output system
Brain activation - SI, SII -
discrimation and intensity
of pain; anterior cingulate
cortex, insula and frontal
cortex - emotional aspects
of pain
5. • In chronic pain, usually, there is no (or
little) peripheral damage, injury or
inflammation - it is a result of nervous
system dysfunction
• Chronic pain is a result of maladaptive
plasticity
6. Clinical examples
• Clinical conditions of chronic pain in which
the pathophysiology is maladaptive plastic
mechanisms
- Phantom limb pain
- Fybromyalgia
- Pain in spinal cord injury
- Pain in stroke
7. How to revert
nervous system
dysfunction
associated with
chronic pain?
TENS
Melzack and
Wall - gate
theory
Spinal cord
stimulation
Vagal nerve
stimulation?
Deep Brain
Stimulation
Cortical
stimulation -
noninvasive
and invasive
techniques
8. Cortical Stimulation for the
treatment of pain
• Initial experience with invasive stimulation - epidural
stimulation of motor cortex is effective to reduce chronic
pain (Tsubokawa, 1993)
• Animal study - the spinal cord was transected -
hyperactivity in the thalamus that was decreased by
motor cortex stimulation, but not sensory stimulation
(Tsubokawa, 1991)
• Neuroimaging study - thalamic modulation associated
with M1 stimulation (Garcia-Larrea, 1999)
17. Initial experience - rTMS
• Cross-over study in which
60 patients with
neuropathic pain received
a single session of active
and sham rTMS
• 10Hz (1000 pulses) rTMS
of the primary motor
cortex - single session
Lefaucheur et al., JNNP, 2004
18. Khedr et al. - JNNP - 2005
Long-lasting effects
• 48 patients - post-
stroke pain and
trigeminal
neuralgia
• 20Hz rTMS of the
primary motor
cortex - 5
consecutive
sessions
19. rTMS for chronic visceral pain
• Initial study - site and
parameters of stimulation
(1Hz - right and left SII
(secondary somatosensory
area; 20 Hz - right and left
SII; sham rTMS)
• Main outcome = %VAS
reduction + % Medication
reduction
Fregni et al., Annals of Neurology, 2005
22. Other strategies
• rTMS for migraine - site of stimulation (left
DLPFC ) - preliminary studies with
significant reduction of migraine attacks
and medication use (Brighina, 2004)
• Other sites of stimulation - comparison of
M1, SI, SMA and PM - pain reduction only
after M1 stimulation (Hirayama, 2006)
• Prediction tool for epidural stimulation
(Andre-Obadia, 2006)
23. Pooled analysis - meta-analysis
• Studies
investigating M1
stimulation for
chronic pain (rTMS
and tDCS)
• 12 studies using
nonivasive brain
stimulation
Risk ratio (responders rate) - active vs. sham rTMS - 2.64, 95% C.I., 1.63 – 4.30
24. Invasive vs. noninvasive brain
stimulation
• 12 studies using non-invasive brain
stimulation and 22 for invasive brain
stimulation (open studies)
• Weighted responders rate:
– 72.6% (95% C.I., 67.7 – 77.4) invasive stimulation
studies
– 45.3% (95% C.I., 39.2 – 51.4) noninvasive
stimulation studies
(36.8% (95% C.I., 30.5 – 43.0) for the rTMS studies and
71.4% (95% C.I., 52.1– 90.7) for tDCS studies)
27. Study design
• 17 patients with spinal cord injury and refractory chronic
pain
• Randomized (1:2) to receive sham and active tDCS
• Baseline evaluation (2 weeks before)
• Treatment (5 days of treatment)
• Follow-up evaluation (after 2 weeks of treatment)
29. tDCS of the primary motor cortex for the treatment of central pain due
to spinal cord injury - Fregni et al., Pain, 2006
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*
*
*
*
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30.
31. tDCS and fibromyalgia
• Extensive evidence suggests that fibromyalgia is associated with a central
nervous system dysfunction:
• Recent evidence has shown that fibromyalgia is associated with specific brain
activity changes. In a recent SPECT study, patients with fibromyalgia as
compared to healthy controls showed a decrease in the regional cerebral blood
flow in the thalamus, caudate nucleus and pontine tegmentum (1). I
• In addition it has long been demonstrated that antidepressants, such as
tricyclics, improve pain in fibromyalgia (2) and recent studies suggest that
centrally acting drugs such as dopaminergic drugs are effective in alleviating
the symptoms of fibromyalgia as compared with placebo (3).
• Finally, this disorder is extremely refractroctory to peripheral treatments such
as non-steroidal anti-inflamatory drugs 31
32. Methods
• Thirty-two patients (females only – mean age of 53.4 ±
8.9 years) participated in this study.
• The following assessments were made: pain
measurement, quality-of-life/other domains of
fibromyalgia, psychiatric symptoms, cognitive and
safety evaluation and adverse events.
• Sleep assessment - polysomnography
• Stimulation - a constant current of 2mA intensity for 20
minutes - 3 groups:
• Anodal M1
• Anodal DLPFC
• Sham tDCS
32
33. Results - main outcome (pain)
The type 3 test of fixed effects revealed a significant effect of time
(p<0.0001), group (p=0.007) and interaction term time vs. group (p<0.0001)
36. Questions
• Long-lasting effect?
• Efficacy of stimulation to other, non-
sensorimotor cortical targets?
• Optimum timing of the brain stimulation?
• Brain stimulation for acute pain?
37. What we don’t know about
chronic pain?
• Individual variability - why some
individuals develop chronic pain - nature
vs. nurture
• Is there specific neural circuits associated
with different chronic pain syndromes -
resolution of neuroimaging tools are not
suficient
• Is it possible to cure chronic pain
38. Is it the perfect therapy for
chronic pain?
• Far from it…
• Effects sizes are still modest
• Adverse effects associated with long-term
use
• Loss of efficacy
• Is there a tolerability for brain stimulation?
40. Redesigning TMS technology
• Coils that can induce an electric current in deep areas -
e.g. cone coils
• Changing pulse configuration - unidirectional
square pulse might improve the efficacy of this
method
• Continuous vs. variable frequency
• Modeling the electrical current
41. Methods of monitoring TMS treatment
• Neuroimaging techniques (SPECT, PET,
fMRI) - “on-line”
Bestmann et al., Neuroimage. 2005
• “off-line” (immediate response or long-
term treatments such as depression
treatment)
Fregni et al. Neurology. 2006 (in press)
• Spectroscopy to measure metabolite
changes
42. EEG-guided TMS system
EEG system to control TMS parameters Analysis of the TMS response - comparison
between motor vs. prefrontal cortex
(Kahkonen et al., Psychopharmacology (Berl), 2005)
Klimesch et al showed that stimulation
at alpha +1Hz frequency induces a
larger cognitive performance gain
43. Enhancing rTMS effects
- Effects of rTMS might be due to
synaptic strengthening
(LTP/LTD).
- Baseline cortical activity would be
an important predictor of the
subsequent effects of rTMS
Iyer et al., J Neurosci. 2003
45. Theta burst stimulation
Theta burst stimulation of the motor cortex produces a long-lasting and powerful effect
on motor cortex physiology
Huang et al., Neuron, 2005
46. Maintenance therapy - what to do after
the induction phase?
• Recent studies showing that rTMS if applied once every
1 or 2 weeks is effective to maintain the beneficial
therapeutic effects
O'Reardon JP, Blumner KH, Peshek AD, Pradilla RR, Pimiento PC. Long-term maintenance therapy
for major depressive disorder with rTMS.J Clin Psychiatry. 2005 Dec;66(12):1524-8.
Li X, Nahas Z, Anderson B, Kozel FA, George MS. Can left prefrontal rTMS be used as a
maintenance treatment for bipolardepression?Depress Anxiety. 2004;20(2):98-100.
• Our experience shows that it is possible to maintain
patients in remission for several years using rTMS
48. • Although there are some encouraging
results, neuromodulation for chronic pain
is still a relatively unexplored field and
conclusions regarding its clinical effects at
this stage are not yet possible.
